Loss of Dok-3 in Non-tumor Cells Induces Malignant Transformation of Benign Epithelial Tumor Cells of the Intestine

The fundamental difference between benign and malignant tumors lies in their invasive ability. It is believed that malignant conversion of benign tumor cells is induced by a tumor cell–intrinsic accumulation of driver gene mutations. Here, we found that disruption of the Dok-3 tumor suppressor gene led to malignant progression in the intestinal benign tumor model ApcMin/+ mice. However, Dok-3 gene expression was undetectable in epithelial tumor cells and the transplantation of bone marrow cells lacking the Dok-3 gene–induced malignant conversion of epithelial tumor cells in ApcMin/+ mice, indicating a previously unrecognized tumor cell–extrinsic mechanism. Moreover, the Dok-3 loss–induced tumor invasion in ApcMin/+ mice required CD4(+) and CD8(+) T lymphocytes, but not B lymphocytes. Finally, whole-genome sequencing showed an indistinguishable pattern and level of somatic mutations in tumors irrespective of the Dok-3 gene mutation in ApcMin/+ mice. Together, these data indicate that Dok-3 deficiency is a tumor-extrinsic driving force of malignant progression in ApcMin/+ mice, providing a novel insight into microenvironments in tumor invasion. SIGNIFICANCE: This study uncovers tumor cell–extrinsic cues that can induce malignant conversion of benign tumors without intensifying mutagenesis in tumors, a novel concept potentially providing a new therapeutic target in malignancy.